Amyloidosis is a serious and usually fatal disease caused by the extracellular accumulation in the tissues of abnormal insoluble protein fibres known as amyloid fibrils. These are derived from more than 20 different proteins in different forms of the disease but all amyloid fibrils share a common cross-β core structure and all are derived by misfolding of normally soluble precursor proteins (Pepys, M. B. (2006) Annu. Rev. Med., 57: 223-241). A normal non-fibrillar plasma protein, serum amyloid P component (SAP), is also always present in amyloid deposits by virtue of its avid specific calcium dependent binding to all types of amyloid fibrils (Pepys et al. (1979) Clin. Exp. Immunol., 38: 284-293; Pepys et al. (1997) Amyloid: Int. J. Exp. Clin. Invest., 4: 274-295).
Human SAP is a constitutive protein in the plasma, at a concentration of around 20-40 mg/l (Nelson et al. (1991) Clin. Chim. Acta, 200:191-200) and with a total of about 50-100 mg of SAP in the combined plasma and extravascular compartments both of normal individuals and patients with diseases other than amyloidosis (Hawkins et al. (1990) J. Clin. Invest., 86: 1862-1869). In patients with amyloidosis, SAP is also specifically concentrated in the amyloid deposits and in an individual with extensive systemic amyloidosis there may be as much as 20,000 mg of SAP in the amyloid (Pepys et al. (1994) PNAS, 91: 5602-5606), reversibly bound to the fibrils and in equilibrium with the fluid phase SAP pool. The normal physiological function of circulating SAP is poorly understood, but animal experiments and in vitro studies suggest a role in host defence (Noursadeghi et al. (2000) PNAS, 97: 14584-14589)). SAP is also a normal tissue matrix constituent associated with elastic fibres and the glomerular basement membrane although its function there is not known.
In amyloidosis, the extracellular amyloid deposits cause disease by progressive accumulation until they damage the structure and thus the function of whatever tissue they occupy (Pepys, M. B. (2006) Annu. Rev. Med., 57: 223-241). There is very rarely any inflammatory or ‘foreign body’ response to amyloid deposition, either seen locally in the tissues or suggested by systemic markers of inflammation. Systemic amyloidosis can involve any organ, is usually fatal and causes ˜1 per thousand deaths in developed countries. Localised amyloid, confined to a single anatomical location or tissue type, can also be very serious, for example cerebral amyloid angiopathy is an important cause of haemorrhagic stroke. The clinical presentations of amyloidosis are extremely diverse and the diagnosis is rarely made before significant organ damage is present. Over 20 different amyloid fibril proteins are responsible for different forms of amyloidosis, but treatments that substantially reduce the abundance of the respective amyloid fibril precursor protein do halt amyloid accumulation and the deposits may regress. Unfortunately effective measures are not always available and, when they do exist, are toxic or hazardous and slow to act (Pepys, M. B (2006) Annu. Rev. Med., 57: 223-241). There is therefore a major unmet medical need for therapy which safely promotes the clearance of established amyloid deposits. Furthermore, there are other conditions in which amyloid deposits are always present, most importantly Alzheimer's disease (AD) and type 2 diabetes mellitus, in which the contribution of amyloid deposition to the pathogenesis of disease, specifically loss of cognitive and pancreatic islet function, respectively, is not known (Pepys, M. B. (2006) Annu. Rev. Med., 57: 223-241). However, amyloid deposits anywhere else in the body are demonstrably pathogenic and it is likely that the cerebral deposits of AD and the islet amyloid deposits of type 2 diabetes are also harmful. Since treatment which clears amyloid deposits in systemic amyloidosis will certainly be therapeutic (Pepys, M. B. (2006) Annu. Rev. Med., 57: 223-241), removal of the amyloid deposits in AD and type 2 diabetes should also be clinically beneficial.
Binding of SAP stabilises amyloid fibrils, protects them from proteolysis in vitro (Tennent et al., (1995) PNAS, 92: 4299-4303), can enhance amyloid fibrillogenesis in vitro (Myers et al., (2006), Biochemistry, 45: 2311-2321) and contributes to pathogenesis of systemic amyloidosis in vivo (Botto et al., (1997) Nature Med., 3: 855-859). Coupled with its universal presence in all amyloid deposits, these properties of SAP make it an attractive therapeutic target.
European patent application EP 0915088 discloses D-proline derivative compounds that are competitive inhibitors of binding of SAP to amyloid fibrils, as well as methods for their manufacture. A preferred compound disclosed in EP 0915088 is (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo oxohexanoyl] pyrrolidine-2-carboxylic acid (CPHPC).
International patent application WO 03/051836 discloses prodrugs for D-proline derivative compounds.
International patent application WO 2004/099173 discloses glycerol cyclic pyruvate derivatives that are competitive inhibitors of binding of SAP to amyloid fibrils.
International patent application WO 04/059318 describes methods which are asserted to enhance fibrocyte formation which comprise the provision of compositions which bind SAP. Such compositions include anti-SAP antibodies and CPHPC. WO 04/059318 does not disclose the treatment of disease associated with amyloid deposition. Furthermore, there is compelling clinical and in vivo evidence that neither SAP nor its depletion have any effect on fibrosis in humans (Tennent et al., (2007) Arthritis Rheum., 56: 2013-2017; Pepys, M. B., Tennent, G. A. and Denton, C. P. (2007) Reply to Letter from Pilling, D., Buckley, C. D., Salmon, M. and Gomer, R. G., Serum amyloid P and fibrosis in systemic sclerosis: comment on the article by Tennent et al. Arthritis Rheum., 56: 4229-4230).
The bis-D-proline compound, CPHPC, disclosed in the patents listed above, is bound with high affinity by human SAP and was intended as a drug to remove SAP from amyloid deposits in vivo and thereby facilitate their clearance. Binding of CPHPC by SAP triggers rapid clearance of the complex by the liver, depletes almost all circulating SAP for as long as the drug is administered, and removes much but not all amyloid bound SAP (Pepys et al., (2002) Nature, 417: 254-259). In initial clinical studies (Gillmore et al., (2010) Brit. J. Haematol., doi:10.1111/j.1365-2141.2009.08036.x), administration of CPHPC seemed to arrest amyloid accumulation but it did not produce amyloid regression and since CPHPC does not completely remove all SAP from amyloid deposits, another approach is needed.
International patent application WO 2009/000926 discloses the use of compounds which deplete SAP from the circulation, such as D-proline derivatives, in particular CPHPC, in combination with an antibody specific for SAP for the treatment or prophylaxis of amyloidosis.
Related International patent application PCT/EP2008/011135 concerns various mouse monoclonal antibodies which may be used in combination with compounds which deplete SAP from the circulation, such as D-proline derivatives, in particular CPHPC, for the treatment or prophylaxis of amyloidosis.
Accordingly, there is a need in the art for antibodies, particularly humanised or human antibodies, which specifically target SAP and provide improved therapeutic efficacy in patients, particularly human patients, with diseases associated with amyloid deposition in order to preserve organ function and prolong life.